SSc-related Interstitial Lung Disease Research Articles

Nintedanib downregulates the profibrotic M2 phenotype in cultured monocyte-derived macrophages obtained from systemic sclerosis patients affected by interstitial lung disease

BackgroundSystemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of skin and several internal organs, including lungs. Macrophages are the main cells involved in the immune-inflammatory damage of skin and lungs, and alternatively activated (M2) macrophages seem to have a profibrotic role through the release of profibrotic cytokines (IL10) and growth factors (TGFβ1). Nintedanib is a tyrosine kinase inhibitor targeting several fibrotic mediators and it is approved for the treatment of SSc-related interstitial lung disease (ILD). The study aimed to evaluate the effect of nintedanib in downregulating the profibrotic M2 phenotype in cultured monocyte-derived macrophages (MDMs) obtained from SSc-ILD patients.MethodsFourteen SSc patients, fulfilling the 2013 ACR/EULAR criteria for SSc, 10 SSc patients affected by ILD (SSc-ILD pts), 4 SSc patients non affected by ILD (SSc pts no-ILD), and 5 voluntary healthy subjects (HSs), were recruited at the Division of Clinical Rheumatology-University of Genova, after obtaining Ethical Committee approval and patients’ informed consent. Monocytes were isolated from peripheral blood, differentiated into MDMs, and then maintained in growth medium without any treatment (untreated cells), or treated with nintedanib (0.1 and 1µM) for 3, 16, and 24 h. Gene expression of macrophage scavenger receptors (CD204, CD163), mannose receptor-1 (CD206), Mer tyrosine kinase (MerTK), identifying M2 macrophages, together with TGFβ1 and IL10, were evaluated by quantitative real-time polymerase chain reaction. Protein synthesis was investigated by Western blotting and the level of active TGFβ1 was evaluated by ELISA. Statistical analysis was carried out using non-parametric Wilcoxon test.ResultsCultured untreated SSc-ILD MDMs showed a significant increased protein synthesis of CD206 (p < 0.05), CD204, and MerTK (p < 0.01), together with a significant upregulation of the gene expression of MerTK and TGFβ1 (p < 0.05; p < 0.01) compared to HS-MDMs. Moreover, the protein synthesis of CD206 and MerTK and the gene expression of TGFβ1 were significantly higher in cultured untreated MDMs from SSc-ILD pts compared to MDMs without ILD (p < 0.05; p < 0.01). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly downregulated the gene expression and protein synthesis of CD204, CD206, CD163 (p < 0.05), and MerTK (p < 0.01) compared to untreated cells after 24 h of treatment. Limited to MerTK and IL10, both nintedanib concentrations significantly downregulated their gene expression already after 16 h of treatment (p < 0.05). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly reduced the release of active TGFβ1 after 24 h of treatment (p < 0.05 vs. untreated cells).ConclusionsIn cultured MDMs from SSc-ILD pts, nintedanib seems to downregulate the profibrotic M2 phenotype through the significant reduction of gene expression and protein synthesis of M2 cell surface markers, together with the significant reduction of TGFβ1 release, and notably MerTK, a tyrosine kinase receptor involved in lung fibrosis.

Systemic sclerosis, silica exposure and cellular therapies: The sand in the gears?

Systemic sclerosis (SSc) is a chronic orphan autoimmune disease with the highest mortality rate among rheumatic diseases. SSc-related interstitial-lung disease (ILD) remains among the leading causes of SSc-related mortality with still few therapeutic effective strategies. In patients with crystallin silica exposure, SSc is recognized as an occupational disease according to the French social security system (Table 25A of the general insurance regimen). Lympho-ablative or myeloablative immunosuppression followed by autologous hematopoietic stem-cell transplantation (aHSCT) is the only therapeutic approach with demonstrated efficacy, improved survival with disease modifying effects on SSc-fibrotic manifestations (skin disease and ILD) and quality of life. A documented past and/or present occupational silica exposure, with extensive exposure and/or silica-related ILD and/or with persistent silica content in the broncho-alveolar lavage fluid are contra-indications to aHSCT in SSc patients, due to the risk of silica-related malignancy or of SSc relapse. This article aims to discuss alternative options in SSc patients with a history of silica exposure, and how innovative cellular therapies (mesenchymal stromal cells, CAR cells) could represent new therapeutic options for these patients.

Protein profiling in systemic sclerosis patients with different pulmonary complications using proteomic antibody microarray

BackgroundPulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are leading causes of systemic sclerosis (SSc)-related death. In this study, we aimed to identify biomarkers for detecting SSc pulmonary complications that are mild and in the early stages to improve the prognosis.MethodsWe screened for serum biomarkers using a proteomic antibody microarray that simultaneously assessed 1000 proteins. Differentially expressed proteins were further verified using ELISA. Finally, we performed a correlation analysis using clinical data.ResultsWe identified 125 differentially expressed proteins, of which calcitonin, sclerostin (SOST), CD40, and fibronectin were selected for further verification. Serum calcitonin and SOST levels were significantly elevated in all SSc pulmonary complication subgroups, whereas serum calcitonin levels were higher in the SSc with PAH subgroup than in the SSc without PAH and ILD subgroup. Serum SOST levels were possibly associated with the presence of ILD and positively related to the presence of cardiac and gastrointestinal involvement. Serum CD40 and calcitonin levels appeared to be positively related to the presence of renal involvement, and serum calcitonin was also positively related to the presence of gastrointestinal involvement.ConclusionsThis study indicated that serum calcitonin and SOST levels may be promising biomarkers for SSc-related PAH and ILD, respectively. Further research is needed to verify this result and understand the underlying mechanisms.

Enrichment strategies for clinical trials targeting skin fibrosis and interstitial lung disease in systemic sclerosis.

This review gives an update on enrichment strategies for clinical trials in patients with systemic sclerosis (SSc) in two contexts - skin fibrosis in early diffuse cutaneous disease, and SSc-related interstitial lung disease (ILD) - focusing on reports from the last 18 months. Lessons have been learnt from recent studies, making this review timely. Recent trials have highlighted how patients included into trials must be carefully selected to include 'progressors', that is, those most likely to benefit from treatment, and how drug mechanism action of action will influence trial design. For skin fibrosis, current enrichment strategies are mainly on clinical grounds (including disease duration, extent of skin thickening, tendon friction rubs and anti-RNA polymerase III positivity). Gene expression signatures may play a role in the future. For ILD, current enrichment strategies (degree of lung involvement as assessed by pulmonary function and high-resolution computed tomography) may help to recruit the most informative patients, but should avoid being too stringent to be feasible or for findings to be generalizable. Both skin fibrosis and ILD trials are challenging in SSc. Ongoing work on enrichment strategies should help to differentiate effective new treatments from placebo with smaller sample sizes than have been included in recent studies.

Combining Clinical and Biological Data to Predict Progressive Pulmonary Fibrosis in Patients With Systemic Sclerosis Despite Immunomodulatory Therapy.

Progressive pulmonary fibrosis (PPF) is the leading cause of death in systemic sclerosis (SSc). This study aimed to develop a clinical prediction nomogram using clinical and biological data to assess risk of PPF among patients receiving treatment of SSc-related interstitial lung disease (SSc-ILD). Patients with SSc-ILD who participated in the Scleroderma Lung Study II (SLS II) were randomized to treatment with either mycophenolate mofetil (MMF) or cyclophosphamide (CYC). Clinical and biological parameters were analyzed using univariable and multivariable logistic regression, and a nomogram was created to assess the risk of PPF and validated by bootstrap resampling. Among 112 participants with follow-up data, 22 (19.6%) met criteria for PPF between 12 and 24 months. An equal proportion of patients randomized to CYC (n=11 of 56) and mycophenolate mofetil (n=11 of 56) developed PPF. The baseline severity of ILD was similar for patients who did, compared to those who did not, experience PPF in terms of their baseline forced vital capacity percent predicted, diffusing capacity for carbon monoxide percent predicted, and quantitative radiological extent of ILD. Predictors in the nomogram included sex, baseline CXCL4 level, and baseline gastrointestinal reflux score. The nomogram demonstrated moderate discrimination in estimating the risk of PPF, with a C-index of 0.72 (95% confidence interval 0.60-0.84). The SLS II data set provided a unique opportunity to investigate predictors of PPF and develop a nomogram to help clinicians identify patients with SSc-ILD who require closer monitoring while on therapy and potentially an alternative treatment approach. This nomogram warrants external validation in other SSc-ILD cohorts to confirm its predictive power.

Prognostic value of automated assessment of interstitial lung disease on CT in systemic sclerosis.

Stratifying the risk of death in SSc-related interstitial lung disease (SSc-ILD) is a challenging issue. The extent of lung fibrosis on high-resolution CT (HRCT) is often assessed by a visual semiquantitative method that lacks reliability. We aimed to assess the potential prognostic value of a deep-learning-based algorithm enabling automated quantification of ILD on HRCT in patients with SSc. We correlated the extent of ILD with the occurrence of death during follow-up, and evaluated the additional value of ILD extent in predicting death based on a prognostic model including well-known risk factors in SSc. We included 318 patients with SSc, among whom 196 had ILD; the median follow-up was 94 months (interquartile range 73-111). The mortality rate was 1.6% at 2 years and 26.3% at 10 years. For each 1% increase in the baseline ILD extent (up to 30% of the lung), the risk of death at 10 years was increased by 4% (hazard ratio 1.04, 95% CI 1.01, 1.07, P = 0.004). We constructed a risk prediction model that showed good discrimination for 10-year mortality (c index 0.789). Adding the automated quantification of ILD significantly improved the model for 10-year survival prediction (P = 0.007). Its discrimination was only marginally improved, but it improved prediction of 2-year mortality (difference in time-dependent area under the curve 0.043, 95% CI 0.002, 0.084, P = 0.040). The deep-learning-based, computer-aided quantification of ILD extent on HRCT provides an effective tool for risk stratification in SSc. It might help identify patients at short-term risk of death.

Critical Role of LMCD1 in Promoting Profibrotic Characteristics of Lung Myofibroblasts in Experimental and Scleroderma-Associated Lung Fibrosis.

Interstitial lung disease (ILD) is a serious complication and leading cause of mortality in patients with systemic sclerosis (SSc). In this study, we explored the role of LIM and cysteine-rich domains protein 1 (LMCD1) as a novel factor in the pathogenesis of SSc-related ILD (SSc-ILD). The expression and effects of LMCD1 were studied in lung tissue samples and fibroblasts from SSc-ILD patients and control subjects as well as in lung tissue samples from animal models. LMCD1 was consistently elevated in lung tissue samples and in fibroblasts isolated from SSc-ILD patients as compared to controls. Additionally, LMCD1 was found to be highly expressed in the lung in the fibroblast-specific protein (FSP)-driven, constitutively active transforming growth factor β receptor type I (TGFβR1) transgenic mouse model of ILD and the bleomycin-induced mouse model of ILD. In lung fibroblasts from SSc-ILD patients, LMCD1 is an essential factor for the TGFβ-induced generation of type I collagen, fibronectin, and α-smooth muscle actin (α-SMA). Depletion of LMCD1 by small interfering RNA reduced the expression of extracellular matrix proteins and lowered transcriptional activity and expression of α-SMA, as well as decreased the proliferation and contractile activity of SSc-ILD lung fibroblasts. In dense fibrotic areas of affected lung tissue, lung LMCD1 colocalized with α-SMA. In cultured scleroderma lung fibroblasts, LMCD1 colocalized and interacted with serum response factor which mediates LMCD1-induced contractile activity of lung fibroblasts. Our study identifies LMCD1 as a profibrotic molecule contributing to the activation of myofibroblasts and the persistent fibroproliferation observed in SSc-ILD. Thus, LMCD1 may be a potential novel therapeutic target for patients with SSc-ILD.

Serum levels of interleukin 17 and 22 in patients with systemic sclerosis: a single-center cross-sectional study.

Systemic sclerosis (SSc) is a chronic, autoimmune disease characterized by inflammation, vasculopathy, and fibrosis of the skin and internal organs. Immunological response in SSc is still poorly understood. Cytokines play a significant role in this process leading to vasculopathy and fibrosis. In this cross-sectional study, we aimed to investigate serum levels of Th-17-related cytokines, IL-17 and IL-22, and to determine their correlation to the clinical association in SSc patients. Serum IL-17 and IL-22 levels were examined in 42 SSc patients and 29 healthy individuals. Associations between serum IL-17 and IL-22 levels and the duration of the disease, the extent of skin fibrosis, capillaroscopic findings, and involvement of the internal organs were explored.Serum IL-17 levels were not different in SSc and the control group. Serum IL-22 levels were significantly elevated in SSc patients compared to healthy individuals (p = 0.04). A positive correlation was found between the IL-22 sera levels and interstitial lung disease (p = 0.007). These results suggest IL-22 as a potential biomarker in SSc-related interstitial lung disease.

Dual-energy CT lung perfusion in systemic sclerosis: preliminary experience in 101 patients.

To investigate lung perfusion in systemic sclerosis (SSc). The study population included 101 patients who underwent dual-energy CT (DECT) in the follow-up of SSc with pulmonary function tests obtained within 2 months. Fifteen patients had right heart catheterization-proven PH. Thirty-seven patients had no SSc-related lung involvement (Group A), 56 patients had SSc-related interstitial lung disease (Group B) of variable extent (Group B mild: ≤ 10% of lung parenchyma involved: n = 17; Group B moderate: between 11 and 50%: n = 31; Group B severe: > 50%: n = 8), and 8 patients had PVOD/PCH (Group C). Lung perfusion was abnormal in 8 patients in Group A (21.6%), 14 patients in Group B (25%), and 7 patients in Group C (87.5%). In Group A and Group B mild (n = 54), (a) patients with abnormal lung perfusion (n = 14; 26%) had a higher proportion of NYHA III/IV scores of dyspnea (7 [50%] vs 7 [17.5%]; p = 0.031) and a shorter mean walking distance at the 6MWT (397.0 [291.0; 466.0] vs 495.0 [381.0; 549.0]; p = 0.042) but no evidence of difference in the DLCO% predicted (61.0 [53.0; 67.0] vs 68.0 [61.0; 78.0]; p = 0.055) when compared to patients with normal lung perfusion (n = 40; 74%); (b) a negative correlation was found between the iodine concentration in both lungs and the DLCO% predicted but it did not reach statistical significance (r = -0.27; p = 0.059) and no correlation was found with the PAPs (r = 0.16; p = 0.29) and walking distance during the 6MWT (r = -0.029; p = 0.84). DECT lung perfusion provides complementary information to standard HRCT scans, depicting perfusion changes in SSc patients with normal or minimally infiltrated lung parenchyma. • In a retrospective observational study of 101 consecutive patients with SSc, dual-energy CT pulmonary angiography was obtained to evaluate lung perfusion. • Lung perfusion was abnormal in 14 out of 54 patients (26%) with no or mild SSc-related lung infiltration. • Patients with abnormal perfusion and no or mild SSc-related lung infiltration had more severe scores of dyspnea and shorter walking distance than patients with similar lung findings and normal perfusion, suggesting the presence of small vessel vasculopathy.

Myeloid cell-specific deletion of Capns1 prevents macrophage polarization toward the M1 phenotype and reduces interstitial lung disease in the bleomycin model of systemic sclerosis

BackgroundCalpains are a family of calcium-dependent thiol proteases that participate in a wide variety of biological activities. In our recent study, calpain is increased in the sera of scleroderma or systemic sclerosis (SSc). However, the role of calpain in interstitial lung disease (ILD) has not been reported. ILD is a severe complication of SSc, which is the leading cause of death in SSc. The pathogenesis of SSc-related ILD remains incompletely understood. This study investigated the role of myeloid cell calpain in SSc-related ILD.MethodsA novel line of mice with myeloid cell-specific deletion of Capns1 (Capns1-ko) was created. SSc-related ILD was induced in Capns1-ko mice and their wild-type littermates by injection 0.l mL of bleomycin (0.4 mg/mL) for 4 weeks. In a separate experiment, a pharmacological inhibitor of calpain PD150606 (Biomol, USA, 3 mg/kg/day, i.p.) daily for 30 days was given to mice after bleomycin injection on daily basis. At the end of the experiment, the animals were killed, skin and lung tissues were collected for the following analysis. Inflammation, fibrosis and calpain activity and cytokines were assessed by histological examinations and ELISA, and immunohistochemical analyses, western blot analysis and Flow cytometry analysis.ResultsCalpain activities increased in SSc-mouse lungs. Both deletion of Capns1 and administration of PD150606 attenuated dermal sclerosis as evidenced by a reduction of skin thickness and reduced interstitial fibrosis and inflammation in bleomycin model of SSc mice. These effects of reduced calpain expression or activity were associated with prevention of macrophage polarization toward M1 phenotype and consequent reduced production of pro-inflammatory cytokines including TNF-α, IL-12 and IL-23 in lung tissues of Capns1-ko mice with bleomycin model of SSc. Furthermore, inhibition of calpain correlated with an increase in the protein levels of PI3K and phosphorylated AKT1 in lung tissues of the bleomycin model of SSc mice.ConclusionsThis study for the first time demonstrates that the role of myeloid cell calpain may be promotion of macrophage M1 polarization and pro-inflammatory responses related PI3K/AKT1 signaling. Thus, myeloid cell calpain may be a potential therapeutic target for bleomycin model of SSc-related ILD.

Favorable long term effects of intensified immunosuppression combined with therapeutic plasma exchange in patients with early-onset progressive systemic sclerosis-related interstitial lung disease

ObjectiveSystemic sclerosis (SSc) related mortality and morbidity remains high. Immunosuppressive therapy is considered most effective when immune activity and inflammation but not fibrosis still dominates the disease process. This study evaluated long-term intensified immunosuppression combined with therapeutic plasma exchange (TPE) in early-onset progressive SSc-related interstitial lung disease (ILD). MethodsThe study cohort consisted of 161 SSc patients, with a median follow-up time of 8.9 years. The standardized mortality rate (SMR) and overall survival was calculated in patients with and without cardiopulmonary involvement. We used a standardized, pragmatic, non-randomized approach to treat 24 consecutive early progressive SSc-ILD patients with intensified immunosuppressive therapy, including plasma exchange. Outcome measurements were event-free survival (EFS), pulmonary function and safety profile. The outcome was compared with the analyzed data from the other SSc-ILD patients, who did not fulfill the inclusion criteria, and instead were treated with estimated optimal care (EOc). ResultsThe age-adjusted SMR of all 161 SSc patients was 3.0 (CI95%; 0.32–5.68). EFS at 10 years was 49.9% in the intensified treatment group and 43.3% in the EOc group (p = 0.106). Improvement of the percentage of predicted forced vital capacity (%pFVC) and percentage of predicted diffusing capacity for carbon monoxide (%pDLco) in the intensified treatment group was +10.1% respectively +3.6%, compared to a decrease of respectively 10.8% and 7% in the EOc (p < 0.001 resp. p = 0.019). Safety analysis showed 1 death (female patient, over 75 years of age), due to pneumosepsis, in the intensified treatment group. ConclusionIntensified and long-lasting immunosuppression combined with TPE is safe in early severe systemic sclerosis and is associated with improved EFS and pulmonary function as compared to the outcome in the variable but EOc group. Our findings warrant larger studies for confirmation.

Lung ultrasound B-lines in systemic sclerosis: cut-off values and methodological indications for interstitial lung disease screening.

Lung ultrasound (LUS), through assessment of B-lines and pleural line alterations, is able to evaluate interstitial lung disease (ILD), a frequent complication of SSc. Different scanning schemes and counting methods have been proposed but no clear cut-off values have been indicated for screening. We aimed to evaluate the accuracy of different LUS methodological approaches to detect ILD compared with high-resolution CT (HRCT) as the gold standard. Sixty-nine SSc patients underwent LUS and chest HRCT on the same day. Both exams were scored by expert readers. The accuracy of different scanning schemes and counting methods was assessed and clinical and functional data were compared with imaging findings. B-lines were more numerous in patients with the diffuse skin subset and Scl70 autoantibody positivity. The number of B-lines correlated with the Scleroderma Lung Study (SLS) I HRCT score (R = 0.754, P < 0.0001). A total of >10 B-lines on the whole chest or >1 B-line on the postero-basal chest showed 97% sensitivity for detecting even very early ILD signs (corresponding to an SLS I score of 1). Sensitivity increased to 100% when pleural line alterations were included in the analysis. LUS has a very high sensitivity in detecting SSc-related ILD. A cut-off value of >10 B-lines on the whole chest or >1 B-line on the postero-basal chest can be used for the screening of SSc-ILD. Assessing only the postero-basal chest seems to be mostly effective, combining high sensitivity with a less time-consuming approach.

A candidate gene study reveals association between a variant of the SRp55 splicing factor gene and systemic sclerosis.

To examine the possible implication of the mRNA-binding protein serine/arginine protein 55 (SRp55, also known as SRSF6) rs2235611 single nucleotide polymorphism (SNP) in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotype. A total population of 872 white Italian individuals (414 SSc patients, 458 controls) was studied. SSc patients were assessed for limited and diffuse cutaneous subsets and the presence of autoantibodies, interstitial lung disease (ILD), and nailfold videocapillaroscopy (NVC) abnormalities. The SRp55 rs2235611 SNP was genotyped by TaqMan real-time PCR. SRp55 rs2235611 genotype distribution and allele frequency were similar in SSc and healthy controls, though a trend toward significance was observed for genotype distribution (p=0.07). The SRp55 rs2235611 AA genotype significantly influenced the predisposition to SSc (p= 0.03). The SRp55 rs2235611 A minor allele and AA genotype showed a significant risk association with susceptibility to SSc-related ILD (A allele: p=0.046; AA genotype: p=0.007). A significant association of the AA genotype with SSc late NVC pattern was also found (p=0.006). After Bonferroni correction for multiple comparisons, the risk association of the SRp55 rs2235611 AA genotype with SSc-related ILD and late NVC pattern remained significant (padj=0.049 and padj=0.042, respectively). The SRp55 rs2235611 AA genotype significantly influences the susceptibility to SSc, and specifically associates with the presence of SSc-related ILD and late NVC pattern. Further in-depth studies on the SRp55 gene locus will hopefully contribute to extend our knowledge of the genetic predisposition to major SSc-related manifestations such as pulmonary fibrosis and peripheral microvasculopathy.

Prediction of a Competing Endogenous RNA Co-expression Network by Comprehensive Methods in Systemic Sclerosis-Related Interstitial Lung Disease.

Systemic sclerosis (SSc) is an immune-mediated connective tissue disease characterized by fibrosis of multi-organs, and SSc-related interstitial lung disease (SSc-ILD) is a leading cause of morbidity and mortality. To explore molecular biological mechanisms of SSc-ILD, we constructed a competing endogenous RNA (ceRNA) network for prediction. Expression profiling data were obtained from the Gene Expression Omnibus (GEO) database, and differential expressed mRNAs and miRNAs analysis was further conducted between normal lung tissue and SSc lung tissue. Also, the interactions of miRNA–lncRNA, miRNA–mRNA, and lncRNA–mRNA were predicted by online databases including starBase, LncBase, miRTarBase, and LncACTdb. The ceRNA network containing 11 lncRNAs, 7 miRNAs, and 20 mRNAs were constructed. Based on hub genes and miRNAs identified by weighted correlation network analysis (WGCNA) method, three core sub-networks—SNHG16, LIN01128, RP11-834C11.4(LINC02381)/hsa-let-7f-5p/IL6, LINC01128/has-miR-21-5p/PTX3, and LINC00665/hsa-miR-155-5p/PLS1—were obtained. Combined with previous studies and enrichment analyses, the lncRNA-mediated network affected LPS-induced inflammatory and immune processes, fibrosis development, and tumor microenvironment variations. The ceRNA network, especially three core sub-networks, may be served as early biomarkers and potential targets for SSc, which also provides further insights into the occurrence, progression, and accurate treatment of SSc at the molecular level.

An update on recent randomized clinical trials in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disorder characterized by a remarkable clinical heterogeneity and variable disease course. In this multifactorial condition, the interaction of several pathogenic pathways related to inflammation, vasculopathy and fibrosis promote organ damage. The understanding of the pathogenesis of SSc has improved in recent years leading to the identification of relevant therapeutic targets. Over the last few years, insightful clinical trials have been published and great progress has been made in developing effective therapeutic options. The positive results of the Safety and Efficacy of Nintedanib in Systemic SClerosIS (SENSCIS) trial have led to the approval by drug agencies of the first drug for SSc-related interstitial lung disease. However, the majority of clinical trials have focused on immunosuppressive therapy. Although benefit trends have been observed, outstanding results have not been achieved and to date no immunosuppressant has been approved in SSc. Clinical trial design has evolved regarding inclusion criteria with the aim to enrich for progressive patients. Endpoints have also been revised to better cover the fields of patients' feelings and functioning. Finally, background synthetic immunosuppressants have been allowed in some trials evaluating targeted therapies opening the door to combination therapies. Herewith, we provide an overview of the most significant clinical trials developed in recent years for the management of SSc.

Elevated Liver Function in a Bilateral Lung Transplant Recipient with Scleroderma: Is the Medication to Blame?

<h3>Introduction</h3> Scleroderma (SSc) is an autoimmune disease that can result in end-stage interstitial lung disease (ILD). Rarely, SSc has been associated with primary sclerosing cholangitis (PSC). Lung transplant may be considered for the advanced treatment of SSc-related ILD. Herein, we describe the case of a lung transplant recipient with SSc who also presented a challenging diagnosis of PSC. <h3>Case Report</h3> The patient is a 47-year-old female bilateral lung transplant recipient with history of SSc-related ILD and pulmonary hypertension. Maintenance immunosuppression consisted of tacrolimus, prednisone, and mycophenolate mofetil, and itraconazole was administered for anti-fungal prophylaxis. Early post-transplant, the patient experienced a tonic-clonic seizure related to tacrolimus toxicity. Decision was made to substitute cyclosporine, and levetiracetam was initiated for seizure prophylaxis. We then observed subtle elevations in her liver function tests. All medications were discontinued, without change in liver function, prompting MRI of the abdomen (Figure 1) which revealed multifocal areas of beaded appearance of the central intrahepatic ducts, suggesting PSC. Liver biopsy revealed focal portal tract fibrosis with bile duct lymphocytic exocytosis and vacuolar change, bile ductular proliferation, focal central venous minimal endothelialitis, and focal lobular necrosis with scattered lobular microgranulomata, with a differential of graft versus host disease. Ursodiol was started, and the patient underwent endoscopic retrograde cholangiopancreatography, which confirmed PSC. With no other interventions, liver function normalized. <h3>Summary</h3> Extrapulmonary sclerosis is a concern in lung transplant recipients with SSc. Esophageal involvement tends to garner the most attention from clinicians, yet this case raises awareness for PSC as a rare condition coincident with SSc. Medication use may be misleading when diagnosing the cause of elevated liver function.

Lung magnetic resonance imaging in systemic sclerosis: a new promising approach to evaluate pulmonary involvement and progression.

Interstitial lung disease (ILD) is frequent and highly disabling in systemic sclerosis (SSc). Magnetic resonance imaging (MRI) is not routinely used to evaluate the lung, due to poorer spatial resolution compared to high-resolution computed tomography (HRCT). We aimed to compare lung MRI signal with HRCT and evaluate the role of MRI in predicting ILD progression. Thirty SSc patients underwent lung MRI and HRCT. STIR and T1 mapping sequences were acquired before and after gadolinium injection. Patients were classified as normal (group 1 with normal HRCT and MRI), discordant (group 2 without ILD signs on HRCT but areas of hyperintensity on MRI), and abnormal (group 3 with ILD signs on HRCT and areas of hyperintensity on MRI). Patients were followed up for ILD progression. Mean STIR and T1 values were different between the three groups (p < 0.0001). STIR values correlated with HRCT score (R = 0.79, p < 0.0001), lung ultrasound B-lines (R = 0.73, p < 0.0001), and %DLco (R = - 0.63, p = 0.0001). Nine events were recorded during a follow-up of 25 ± 20months. Continuous STIR values were independently associated with events (HR 1.018; CI 1.005-1.031, p = 0.005). A STIR value >90ms discriminated patients at a higher risk of worsening pulmonary involvement (HR 8.80; CI 1.81-42.74; p < 0.007). Lung MRI can detect SSc-related ILD, with good correlations with other ILD markers. STIR values, independently of HRCT appearance, may predict worsening lung involvement. Lung MRI, although very preliminary, is a promising tool that in a near future could help selecting patients for an early treatment of SSc-related ILD and a more appropriate use of HRCT. Key points • Lung MRI has the potential to differentiate inflammation-predominant versus fibrosis-predominant lesions, but it is not currently used in routine clinical practice to assess SSc-related ILD. • Lung MRI STIR and T1 values are significantly different between patients with and without SSc-related ILD. STIR values, independently of HRCT appearance, are also able to predict worsening lung involvement over time. • These preliminary data suggest that, in a near future, MRI could support the choice for an early treatment of SSc-related ILD, as well as a more appropriate use of HRCT.

Potential Biomarkers in Systemic Sclerosis: A Literature Review and Update.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by dysregulation of the immune system, vascular damage, and fibrosis of the skin and internal organs. Patients with SSc show a heterogeneous phenotype and a range of clinical courses. Therefore, biomarkers that are helpful for precise diagnosis, prediction of clinical course, and evaluation of the therapeutic responsiveness of disease are required in clinical practice. SSc-specific autoantibodies are currently used for diagnosis and prediction of clinical features, as other biomarkers have not yet been fully vetted. Krebs von den Lungen-6 (KL-6), surfactant protein-D (SP-D), and CCL18 have been considered as serum biomarkers of SSc-related interstitial lung disease. Moreover, levels of circulating brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) can provide diagnostic information and indicate the severity of pulmonary arterial hypertension. Assessment of several serum/plasma cytokines, chemokines, growth factors, adhesion molecules, and other molecules may also reflect the activity or progression of fibrosis and vascular involvement in affected organs. Recently, microRNAs have also been implicated as possible circulating indicators of SSc. In this review, we focus on several potential SSc biomarkers and discuss their clinical utility.

A RETROSPECTIVE DESCRIPTIVE ANALYSIS OF SYSTEMIC SCLEROSIS-RELATED INTERSTITIAL LUNG DISEASE AND PULMONARY HYPERTENSION

SESSION TITLE: Pulmonary Manifestations of Systemic Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Patients with systemic sclerosis (SSc) can present with pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), or a combination of both ILD and pulmonary hypertension (PH). Little is known about the frequency of those who present with each disorder individually and subsequently develop the concurrent condition. We sought to examine the presentation, progression and prognosis between these phenotypes in a cohort of SSc patients. METHODS: We examined a cohort of SSc patients from 2006 to 2016. We further classified this group into those who presented with SSc-ILD alone, PAH alone, and SSc-ILD concomitant with PH on initial consult. Using the most recent right heart catheterization data (RHC), high-resolution CT (HRCT) findings and expert census from the electronic medical record (EMR), we tracked the progression of those who developed ILD and PH. Kaplan-Meier (KM) curves were generated to assess 3-year transplant-free survival with the log-rank test used to compare differences between the groups. RESULTS: There were 53 patients in our cohort who were categorized into 3 groups as follows: SSc-ILD - PH (n = 14), SSc - PAH (n = 13), and SSc-ILD (n = 26). In the SSc – PAH group, 54% (n = 7) went on to develop ILD, while in the SSc-ILD group 38% (n = 10) subsequently developed PH. The 3-year survival for the groups with SSc-ILD - PH (n = 14), SSc-PAH who went onto to develop ILD (n = 7), SSc-PAH who did not go on to develop ILD (n = 6), SSc-ILD who went on to develop PH (n = 10), and SSc-ILD who did not go on to develop PH (n = 16) was 85%, 85%, 83%, 68%, 93%, respectively (p-value = 0.16). CONCLUSIONS: In our cohort of SSc, over half the patients who presented with SSc and PAH developed ILD subsequently. There was a nonsignificant trend towards decreased transplant-free survival in the group who presented with SSc-ILD and went on to develop PH. CLINICAL IMPLICATIONS: The recent approval of the antifibrotic agent Nintedanib for those with SSc-related ILD has opened the door for a new era of disease-modifying therapy. The large percentage of patients with PAH who subsequently developed ILD highlights the importance of monitoring for this and highlights the potential importance of a combined PH and ILD clinic as SSc patients’ disease trajectories are often intertwined. DISCLOSURES: No relevant relationships by Scott Barnett, source=Web Response Advisory Committee Member relationship with Boehringer Ingelheim Please note: $5001 - $20000 Added 04/16/2020 by Christopher King, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Actelion Please note: $5001 - $20000 Added 04/16/2020 by Christopher King, source=Web Response, value=Honoraria Advisory Committee Member relationship with Actelion Please note: $1001 - $5000 Added 04/27/2020 by Christopher King, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Boehringer Ingelheim pharmaceuticals Please note: $1001 - $5000 Added 04/27/2020 by Christopher King, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Actelion Please note: $1001 - $5000 Added 04/27/2020 by Christopher King, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Boehringer Ingelheim Please note: $1001 - $5000 Added 04/27/2020 by Christopher King, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Genentech Please note: $1001 - $5000 Added 04/27/2020 by Christopher King, source=Web Response, value=Honoraria Advisory Committee Member relationship with United therapeutics Please note: $1001 - $5000 Added 04/27/2020 by Christopher King, source=Web Response, value=Consulting fee Consultant relationship with Veracyte Please note: $1001 - $5000 Added 04/03/2020 by Steven Nathan, source=Web Response, value=Honoraria Consultant relationship with United Therapeutics Please note: $5001 - $20000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Consulting fee Consultant relationship with Bellerophon Please note: $5001 - $20000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Roche-Genentech Please note: $5001 - $20000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Boerhinger-Ingelheim Please note: $20001 - $100000 Added 05/27/2020 by Steven Nathan, source=Web Response, value=Honoraria No relevant relationships by Ankush Ratwani, source=Web Response No relevant relationships by Anthony Rowe, source=Web Response Scientific Medical Advisor relationship with Johnson & Johnson Please note: $1001 - $5000 Added 04/22/2020 by Oksana Shlobin, source=Web Response, value=Consulting fee Scientific Medical Advisor relationship with Bayer Please note: $1001 - $5000 Added 04/22/2020 by Oksana Shlobin, source=Web Response, value=Grant/Research Support Scientific Medical Advisor relationship with United Therapeutics Please note: $1001 - $5000 Added 04/22/2020 by Oksana Shlobin, source=Web Response, value=Consulting fee

Prevalence and clinical correlates of small airway obstruction in patients with systemic sclerosis.

This study aims to assess the prevalence and clinical correlates of small airway obstruction (SAO) in patients with systemic sclerosis (SSc). Sixty-nine consecutive patients with SSc (63 women and 6 men) were included. Lung function tests, including assessment of lung diffusing capacity, were performed in all patients. Patients were considered to have SAO when the maximal expiratory flow at 25% of the forced vital capacity (MEF25) was lower than 60% as predicted. High-resolution computed tomography (HRCT) of the lung was performed in all patients with MEF25 < 60%. We assessed the relationship of SAO in our patients with large airway obstruction, decreased lung diffusing capacity, HRCT findings, disease duration, disease subtype, scleroderma-specific antibodies, and smoking. SAO was noticed in 46/69 (66.6%) of patients with SSc. Restrictive lung disease was found in 4/69 (5.8%), obstruction of large airways in 18/69 (26.1%), and decreased lung diffusing capacity in 47/69 (68.1%) of patients. No difference in gender, age, disease duration, disease subtype, and scleroderma-specific antibodies was found between patients with and without SAO. Eighteen out of forty-six (39.1%) patients with SAO had decreased forced expiratory volume in 1 sec (FEV1) and the Tiffeneau-Pinelli index, indicating presence of coexistent large airway obstruction. Twenty out of forty-six (43.5%) patients with SAO had associated decreased lung diffusing capacity, while 8/46 (17.4%) of patients had isolated SAO. HRCT patterns of interstitial lung disease (ILD) were found more frequently in patients with SAO and decreased lung diffusing capacity, compared with patients with SAO and normal diffusing capacity (75% vs 11.5%, p = 0.008). We have noticed that tobacco smokers among SSc patients with SAO have more common associated obstructive lung disease on spirometry (58.8% vs 15.4%, p = 0.004). On the other hand, isolated SAO and SAO associated with impaired diffusing capacity were equally frequent among smokers and non-smokers. Patients with SSc have commonly SAO. It can be considered clinical feature of undiagnosed asthma or chronic obstructive pulmonary disease (COPD), if isolated or associated with large airway obstruction, especially in tobacco smokers. On the other hand, SAO associated with decreased lung diffusing capacity was found to be not related to smoking, and may indicate a possible prominent bronchiolar involvement within SSc-related interstitial lung disease Key Points • Small airway obstruction in patients with systemic sclerosis can be considered a clinical feature of undiagnosed obstructive lung disease, if isolated or associated with large airway obstruction, especially in tobacco smokers. • Obstruction of small airways, associated with decreased lung diffusing capacity, may indicate a possible prominent bronchiolar involvement within systemic sclerosis-related interstitial lung disease.